Cerebrospinal fluid from coma and pre-coma patients with recognized liver disease will be analyzed for intermediates of ammonia/glutamine metabolism with particular attention focused upon concentrations of alpha-ketoglutaramate. Repeated samples from the same patients will also be examined for alpha-ketoglutaramate contents and correlated with the patients' clinical status. Such data should establish whether increased levels of alpha-ketoglutaramate in CSF can be considered diagnostic of hepatic coma. Post-mortem brain specimens will be obtained from patients who die with liver disease and assayed for glutamine transaminase and co-amidase. Such information may help to clarify the nature of the metabolic defect in brain and suggest new modes of therapy. Since there exists no adequate experimental model of human hepatic encephalopathy, we will subject rats to a variety of conditions (chronic hyperammonemia, porta-caval shunt, CCl4 poison) which evoke symptoms resembling the disease in man. Our primary aim will be to determine which treatments increase alpha-ketoglutaramate levels in CSF. Animals will also be pretreated with methionine sulfoximine to inhibit cerebral glutamine synthesis and examined biochemically and histologically to see whether ammonia, per se, or a product of ammonia detoxification is responsible for the glial changes associated with chronic liver failure.